The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis

  1. David Ellinghaus
  2. Frauke Degenhardt
  3. Luis Bujanda
  4. Maria Buti
  5. Agustín Albillos
  6. Pietro Invernizzi
  7. Javier Fernández
  8. Daniele Prati
  9. Guido Baselli
  10. Rosanna Asselta
  11. Marit M Grimsrud
  12. Chiara Milani
  13. Fátima Aziz
  14. Jan Kässens
  15. Sandra May
  16. Mareike Wendorff
  17. Lars Wienbrandt
  18. Florian Uellendahl-Werth
  19. Tenghao Zheng
  20. Xiaoli Yi
  21. Raúl de Pablo
  22. Adolfo Garrido Chercoles
  23. Graduate in Chemistry
  24. Adriana Palom
  25. Alba-Estela Garcia-Fernandez
  26. Francisco Rodriguez-Frias
  27. Alberto Zanella
  28. Alessandra Bandera
  29. Alessandro Protti
  30. Alessio Aghemo
  31. Ana Lleo
  32. Andrea Biondi
  33. Andrea Caballero-Garralda
  34. Andrea Gori
  35. Anja Tanck
  36. Anna Latiano
  37. Anna Ludovica Fracanzani
  38. Anna Peschuk
  39. Antonio Julià
  40. Antonio Pesenti
  41. Antonio Voza
  42. David Jiménez
  43. Beatriz Mateos
  44. Beatriz Nafria Jimenez
  45. Graduate in Biotechnology
  46. Carmen Quereda
  47. Claudio Angelini
  48. Cristina Cea
  49. Aurora Solier
  50. David Pestaña
  51. Elena Sandoval
  52. Elvezia Maria Paraboschi
  53. Enrique Navas
  54. Ferruccio Ceriotti
  55. Filippo Martinelli-Boneschi
  56. Flora Peyvandi
  57. Francesco Blasi
  58. Luis Téllez
  59. Albert Blanco-Grau
  60. Giacomo Grasselli
  61. Giorgio Costantino
  62. Giulia Cardamone
  63. Giuseppe Foti
  64. Serena Aneli
  65. Hayato Kurihara
  66. Hesham ElAbd
  67. Ilaria My
  68. Javier Martin
  69. Jeanette Erdmann
  70. José Ferrusquía-Acosta
  71. Koldo Garcia-Etxebarria
  72. Laura Izquierdo-Sanchez
  73. Graduate in Biochemistry, MS
  74. Laura Rachele Bettini
  75. Leonardo Terranova
  76. Leticia Moreira
  77. Luigi Santoro
  78. Luigia Scudeller
  79. Francisco Mesonero
  80. Luisa Roade
  81. Marco Schaefer
  82. Maria Carrabba
  83. Maria del Mar Riveiro Barciela
  84. Maria Eloina Figuera Basso
  85. Maria Grazia Valsecchi
  86. María Hernandez-Tejero
  87. Marialbert Acosta-Herrera
  88. Mariella D’Angiò
  89. Marina Baldini
  90. Marina Cazzaniga
  91. Martin Schulzky
  92. Maurizio Cecconi
  93. Michael Wittig
  94. Michele Ciccarelli
  95. Miguel Rodríguez-Gandía
  96. Monica Bocciolone
  97. Monica Miozzo
  98. Nicole Braun
  99. Nilda Martínez
  100. Orazio Palmieri
  101. Paola Faverio
  102. Paoletta Preatoni
  103. Paolo Bonfanti
  104. Paolo Omodei
  105. Paolo Tentorio
  106. Pedro Castro
  107. Pedro M. Rodrigues
  108. Aaron Blandino Ortiz
  109. Ricardo Ferrer Roca
  110. Roberta Gualtierotti
  111. Rosa Nieto
  112. Salvatore Badalamenti
  113. Sara Marsal
  114. Giuseppe Matullo
  115. Serena Pelusi
  116. Valter Monzani
  117. Tanja Wesse
  118. Tomas Pumarola
  119. Valeria Rimoldi
  120. Silvano Bosari
  121. Wolfgang Albrecht
  122. Wolfgang Peter
  123. Manuel Romero Gómez
  124. Mauro D’Amato
  125. Stefano Duga
  126. Jesus M. Banales
  127. Johannes R Hov
  128. Trine Folseraas
  129. Luca Valenti
  130. Andre Franke
  131. Tom H Karlsen

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Abstract

Background

Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients.

Methods

We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels.

Results

We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5×10 −8 ) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14×10 −10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95×10 −8 ), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48×10 −4 ) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06×10 −5 ).

Conclusions

We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.31.20114991: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: Differences in recruitment and consent procedures between centers were determined by 1) some centers integrating the project in larger Covid-19 biobanking efforts and others doing dedicated inclusion for this project and 2) variability regarding the local ethical committee handling of anonymization vs. deidentification as well as consent procedures.
    IACUC: Written informed consent was obtained from all study subjects at each center when possible, alternatively exempt as defined by delayed consent, oral consent or consent via next of kin was collected depending on local ethical committee regulations.
    IRB: The following ethical approvals of the project were obtained from the relevant ethics committees: Germany: Kiel (reference number D464/20); Italy: Fondazione IRCCS Cá Granda Ospedale Maggiore Policlinico
    RandomizationWe recruited 998 randomly selected blood donors at Fondazione IRCCS Cá Granda Ospedale Maggiore Policlinico, Milan with no evidence of Covid-19 who were genotyped for the purpose of the present study.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Statistical methods: To take imputation uncertainty into account, we tested for phenotypic associations with allele dosage data separately for both Italian and Spanish case-control panels through the use of PLINK’s logistic regression framework for dosage data (PLINK v1.9).
    PLINK
    suggested: (PLINK, RRID:SCR_001757)
    A fixed-effects meta-analysis was conducted using the meta-analysis tool METAL16 on variants overlapping between both studies using the BETA and its standard error (SE) from the study specific association analyses.
    BETA
    suggested: (BETA, RRID:SCR_007556)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    We are fully aware that the pragmatic aspects leading to feasibility of this massive undertaking in a very short period of time during extreme clinical circumstances of the pandemic led to certain limitations that will be important to explore in follow-up studies. For example, to enable recruitment of study participants, a bare minimum of clinical metadata was requested. For this reason, extensive genotype-phenotype elaboration of current findings could not be performed, and adjustments for all potential sources of bias (e.g. underlying cardiovascular and metabolic factors relevant to Covid-19) could not be done. Furthermore, the alignment of our findings with preliminary reports assessing Covid-19 susceptibility should lead to a critical debate as to phenotype definitions for cases and controls in genetic studies of Covid-19. Also, few restrictions during inclusion were made, leading to genotyped samples having to be excluded due to differing ethnicities (genetically population outliers). That said, we took great care to minimize variability between cases and controls arising from such sources, and that could have been introduced from differences between genotyping platforms29 e.g. limiting our inclusion of controls to those genotyped on the Illumina Global Screening Array, despite thus reducing our statistical power. Further exploration of current findings, both as to their utility in clinical risk profiling of Covid-19 patients and mechanistic understanding of the underlyi...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. ScreenIT

    SciScore for 10.1101/2020.05.31.20114991: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementDifferences in recruitment and consent procedures between centers were determined by 1 ) some centers integrating the project in larger Covid-19 biobanking efforts and others doing dedicated inclusion for this project and 2 ) variability regarding the local ethical committee handling of anonymization vs. deidentification as well as consent procedures .RandomizationWe recruited 998 randomly selected blood donors at Fondazione IRCCS Cá Granda Ospedale Maggiore Policlinico , Milan with no evidence of Covid-19 who were genotyped for the purpose of the present study .Blindingnot detected.Power Analysisnot detected.Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Vall d'Hebron Hospital Research Institute, Barcelona, Spain. Department of Respiratory Diseases, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá, Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Madrid, Spain. Department of Infectious Diseases, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá, Madrid, Spain. Department of Anesthesiology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Respiratory Unit, Milan, Italy. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy. Department Emergency, Anesthesia and Intensive Care, University Milano-Bicocca, ASST-Monza, Italy. Department of Medical Science, Università degli Studi di Torino, Turin, Italy. Institute of Parasitology and Biomedicine Lopez-Neyra, IPBLN-CSIC, Granada, Spain. Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany. DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany. University Heart Center Lübeck, Germany. Stefan-Morsch-Stiftung, 55765 Birkenfeld, Germany. Center of Bioinformatics, Biostatistics and Bioimaging, School of Medicine and Surgery, University of Milano Bicocca, Italy. Phase 1 Research Centre, ASST Monza, School of Medicine and Surgery, University of Milano-Bicocca, Italy. University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Germany. Pneumologia ASST-Monza, University of Milano-Bicocca, Italy. Infectious Diseases Unit, San Gerardo Hospital, Monza, Italy. School of Medicine and Suregery, University of Milano-Bicocca, Italy. Department of Intensive Care, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá, Madrid, Spain. Intensive Care Unit, University Hospital Vall d'Hebron, Barcelona, Spain. Microbiology Department, University Hospital Vall d'Hebron, Barcelona, Spain. Digestive Diseases Unit, Virgen del Rocio University Hospoital, Institute of Biomedicine of Seville, University of Seville, Seville, Spain. Ikerbasque, Basque Foundation for Science, Bilbao, Spain. Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. Section for Gastroenterology, Department of Transplantation Medicine, Division for Cancer medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet.
    Biostatistics
    suggested: (BWH Biostatistics Center, SCR_009680)
    Statistical methods To take imputation uncertainty into account , we tested for phenotypic associations with allele dosage data separately for both Italian and Spanish case-control panels through the use of PLINK’s logistic regression framework for dosage data ( PLINK v1.9).
    PLINK
    suggested: (PLINK, SCR_001757)
    A fixed-effects metaanalysis was conducted using the meta-analysis tool METAL16 on variants overlapping between both studies using the BETA and its standard error ( SE ) from the study specific association analyses .
    BETA
    suggested: (BETA, SCR_007556)

    Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.05.31.20114991v1 on medRxiv